Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients

Abstract

Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV-positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1-42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7-6.1) with 12 patients (11.9%) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p = 0.005), phosphorylated tau (p = 0.008), and 1-42 beta amyloid (p = 0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p = 0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p = 0.035), and 1-42 beta amyloid (1134 vs. 830 pg/mL, p = 0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV-positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations.

Probiotics Differently Affect Gut-Associated Lymphoid Tissue Indolamine-2,3-Dioxygenase mRNA and Cerebrospinal Fluid Neopterin Levels in Antiretroviral-Treated HIV-1 Infected Patients: A Pilot Study

“…To date, the main monocyte activation marker known regarding CNS inflammation in HIV-1 infection is CSF neopterin [22]. In particular, neopterin is a sensitive marker of immune activation, and it is produced by monocyte-derived cells [23]. Neopterin detected in the CSF is originated in the CNS [24], and during HIV-1 infection is expressed at high levels, especially in patients with HAND [25].…”

“…Neopterin detected in the CSF is originated in the CNS [24], and during HIV-1 infection is expressed at high levels, especially in patients with HAND [25]. Despite cART, neopterin persists at higher levels in HIV-1-positive patients compared to healthy controls, although an early decrease of its amount in CSF is observed after initiation of therapy [23]. These data suggest an ongoing HIV-1-related pathological process within the CNS, where a continuous neuroinflammation and axonal degradation occurs, despite cART [24].…”

“…However, the amount of neopterin levels is considered a parameter to monitor the activation of immune system [26,27]. Other studies reported a correlation between CSF neopterin levels and CSF neurofilament light protein (NFL)—a biomarker of neuronal injury—in cART-treated HIV-1-positive patients [23]. Consequently, we chose to measure the neopterin levels in CSF as a marker of the expression of brain immune activation, and our findings show a significant decrease in CSF neopterin levels recorded in all HIV-1-positive patients after 6 months of high concentration multistrain probiotic supplementation.…”

HIV/neuroAIDS biomarkers

“…Of the 12 total studies in the literature that investigated Tau levels in CSF of HIV/neuroAIDS patients, four recent studies show elevations of t-Tau (Gisslén et al , 2009; Peterson et al , 2014; Smith et al , 2014; Steinbrink et al , 2013). Three early studies also show increases in CSF levels of p-Tau in HIV/neuroAIDS (Anthony et al , 2006; Cohen et al , 2015; Patrick et al , 2011), and two other studies show increase in both t-Tau and p-Tau (Brew et al , 2005; Calcagno et al , 2015). The other three studies report no change in the levels of t-Tau or p-Tau in HIV/neuroAIDS patients (Clifford et al , 2009; Green et al , 2000; McNamara et al , 2015).…”

“…Phosphorylation of tau occurs following inflammation, and its hyper-phosphorylated form (p-Tau) detaches from microtubules, destabilizing axons and leading to self-assembly of neurofibrillary tangles (Calcagno et al , 2015). Hyper-phosphorylated Tau detected in tangles is a hallmark of Alzheimer’s disease and detection of elevated total tau (t-Tau) in CSF is considered a valuable biomarker in the diagnosis of AD (Peterson et al , 2014).…”